Maximum Allowed Solvent Accessibilites of Residues in Proteins

By Matthew Z. Tien, A. Meyer, Dariya K. Sydykova, Stephanie J. Spielman, Claus O. Wilke. 2012

473 citations recorded by the source corpus.

The relative solvent accessibility (RSA) of a residue in a protein measures the extent of burial or exposure of that residue in the 3D structure. RSA is frequently used to describe a protein's biophysical or evolutionary properties. To calculate RSA, a residue's solvent accessibility (ASA) needs to be normalized by a suitable reference value for the given amino acid; several normalization scales have previously been proposed. However, these scales do not provide tight upper bounds on ASA values frequently observed in empirical crystal structures. Instead, they underestimate the largest allowed ASA values, by up to 20%. As a result, many empirical crystal structures contain residues that seem to have RSA values in excess of one. Here, we derive a new normalization scale that does provide a tight upper bound on observed ASA values. We pursue two complementary strategies, one based on extensive analysis of empirical structures and one based on systematic enumeration of biophysically allowed tripeptides. Both approaches yield congruent results that consistently exceed published values. We conclude that previously published ASA normalization values were too small, primarily because the conformations that maximize ASA had not been correctly identified. As an application of our results, we show that empirically derived hydrophobicity scales are sensitive to accurate RSA calculation, and we derive new hydrophobicity scales that show increased correlation with experimentally measured scales.

Subfields: Materials Chemistry, Molecular Biology

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Citations in the corpus

The inherent mutational tolerance and antigenic evolvability of influenza hemagglutinin (2014, methodology): “…were calculated by first determining the absolute solvent accessibilities of the residues in the full trimeric HA in PDB 1RVX with the DSSP (Joosten et al., 2011) webserver at http://www.cmbi.ru.nl/hsspsoap/, and then normalizing by the maximum solvent accessibilities given by Tien et al. (2013).”
Deep Mutational Scanning of SARS-CoV-2 Receptor Binding Domain Reveals Constraints on Folding and ACE2 Binding (2020, unknown): “Relative solvent accessibilities were determined by normalizing to the maximum theoretical solvent accessibility of a residue (Tien et al., 2013).”
Functional Constraint Profiling of a Viral Protein Reveals Discordance of Evolutionary Conservation and Functionality (2015, methodology): “SASA was then normalized to the empirical scale reported in [88].”
rawMSA: End-to-end Deep Learning Makes Protein Sequence Profiles and Feature Extraction obsolete (2018, methodology): “We used the theoretical Maximum Accessibility Surface Area (Max ASA) defined in [62] to calculate the RSA from the absolute surface areas (ASA) in the DSSP output and we used [0, 0.”
Deep mutational scanning of SARS-CoV-2 receptor binding domain reveals constraints on folding and ACE2 binding (2020, unknown): “normalizing to the maximum theoretical solvent accessibility of a residue (Tien et al., 2013).”